DISSOCIATION OF THE INCREASED FORMATION OF CARDIAC ADENOSINE 3',5'-MONOPHOSPHATE FROM THE POSITIVE INOTROPIC EFFECT OF NOREPINEPHRINE

¹ Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

The isolated, perfused rat heart was used to study the effects of norepinephrine on myocardial 3', 5'-adenosine monophosphate (cyclic AMP), phosphorylase a activity and cardiac force of contraction in the presence and absence of N-isopropylmethoxamine (IMA). IMA (10 µ/ml of perfusion fluid) did not prevent the inotropic response to norepinephrine (0.03 µg) but blocked the increase in phosphorylase a activity produced by the amine. At higher doses of norepinephrine (0.1 and 03 µg), the elevation in enzyme activity was markedly depressed by IMA, but contractility was not significantly impaired. Cardiac cyclic AMP, phosphorylase a activity and force of contraction were measured 2, 4, 7 and 12 seconds after injection of norepinephrine (0.03 µg). When IMA was present in the perfusion fluid, norepinephrine caused no increase in cyclic AMP at any of the time periods studied and prevented the rise in phosphorylsae a activity which ordinarily occurred at 7 and 12 seconds. The increase in contractility , first evident at 4 seconds, was not blocked by IMA at that time interval or at 7 and 12 seconds after norepinephrine injection. The results of the experiments demonstrate that changes in contractile force of the heart can occur in the absence of increases in intracellular concentrations of cyclic AMP. This finding does not support the hypothesis that the inotropic effects of catecholamines are dependent upon alterations in cyclic AMP.